Treatment and Prevention of Heparin-Induced Thrombocytopenia*

Transcription

1 Supplement ANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES Treatment and Prevention of Heparin-Induced Thrombocytopenia* American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Theodore E. Warkentin, MD; Andreas Greinacher, MD; Andreas Koster, MD; and A. Michael Lincoff, MD This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by > 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecularweight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least /L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C]. (CHEST 2008; 133:340S 380S) Key words: argatroban; bivalirudin; coumarin-induced necrosis; danaparoid; fondaparinux; heparin-induced thrombocytopenia; IgG; lepirudin; low-molecular-weight heparin; unfractionated heparin Abbreviations: ACT activated clotting time; APTT activated partial thromboplastin time; CI confidence interval; CPB cardiopulmonary bypass; DIC disseminated intravascular coagulation; DTI direct thrombin inhibitor; DVT deep venous thrombosis; ECT ecarin clotting time; EIA enzyme immunoassay; EMEA European Agency for the Evaluation of Medicinal Products; FDA Food and Drug Administration; HIPA heparin-induced platelet activation assay; HIT heparin-induced thrombocytopenia; INR international normalized ratio; LMWH low-molecular-weight heparin; OD optical density; OR odds ratio; PCI percutaneous coronary intervention; PE pulmonary embolism; PF4 platelet factor 4; RCT randomized controlled trial; RR relative risk; SC subcutaneous; SRA serotonin release assay; UFH unfractionated heparin; VKA vitamin K antagonist 340S

2 Summary of Recommendations 1.0 Recognition of HIT 1.1 Platelet Count Monitoring for HIT 1.1. For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients receiving heparin who have an estimated risk of HIT of 0.1 to 1.0%, we suggest platelet count monitoring over no platelet count monitoring (Grade 2C) Platelet Count Monitoring of Patients Recently Treated With Heparin For patients who are starting UFH or LMWH treatment and who have received UFH within the past 100 days, or those patients in whom exposure history is uncertain, we recommend obtaining a baseline platelet count and then a repeat platelet count within 24 h of starting heparin over not obtaining a repeat platelet count (Grade 1C) Anaphylactoid Reactions After IV UFH Bolus For patients in whom acute inflammatory, cardiorespiratory, neurologic, or other unusual symptoms and signs develop within 30 min following an IV UFH bolus, we recommend performing an immediate platelet count measurement, and comparing this value to recent prior platelet counts, over not performing a platelet count (Grade 1C) Platelet Count Monitoring in Patients Receiving Therapeutic-Dose UFH *From McMaster University (Dr. Warkentin), Hamilton, ON, Canada; Institute for Immunology and Transfusion Medicine (Dr. Greinacher), Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany; Deutsches Herzzentrum Berlin (Dr. Koster), Berlin, Germany; and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (Dr. Lincoff), The Cleveland Clinic Foundation, Cleveland, OH. Manuscript accepted December 20, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Theodore E. Warkentin, MD, Room I-180A, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, General Site, 237 Barton St E, Hamilton, ON, L8L 2X2 Canada; twarken@mcmaster.ca DOI: /chest For patients who are receiving therapeutic-dose UFH, we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C) Platelet Count Monitoring in Postoperative Patients Receiving UFH Antithrombotic Prophylaxis (Highest Risk Group for HIT) For patients who are receiving postoperative antithrombotic prophylaxis with UFH, ie, the patient population at highest risk for HIT (HIT risk > 1%), we suggest at least everyother-day platelet count monitoring between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C) Platelet Count Monitoring in Patients in Whom HIT is Infrequent (0.1 to 1%) For medical/obstetrical patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH flushes, or medical/obstetrical patients receiving LMWH after first receiving UFH (estimated HIT risk, 0.1 to 1%), we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first), when practical, over less frequent platelet count monitoring (Grade 2C) Platelet Count Monitoring When HIT is Rare ( 0.1%): UFH and LMWH For medical/obstetrical patients who are receiving only LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C) Platelet Count Monitoring When HIT is Rare ( 0.1%): Fondaparinux For patients who are receiving fondaparinux thromboprophylaxis or treatment, we recommend that clinicians do not use routine platelet count monitoring (Grade 1C) Management of Patients in Whom Platelet Counts Are Not Monitored In outpatients who will receive heparin prophylaxis or treatment, informed consent CHEST / 133 / 6/ JUNE, 2008 SUPPLEMENT 341S

3 should include HIT and its typical sequelae (new thrombosis, skin lesions) and the patient should be advised to seek medical advice if these events occur (Grade 2C) Screening for Subclinical HIT Antibody Seroconversion In patients who receive heparin, or in whom heparin treatment is planned (eg, for cardiac or vascular surgery), we recommend against routine HIT antibody testing in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to a potential diagnosis of HIT (Grade 1C) When Should HIT Be Suspected? For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by > 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). 1.2 Special Situation: Anticoagulant Prophylaxis and Platelet Count Monitoring After Cardiac Surgery 1.2. For postoperative cardiac surgery patients, we recommend investigating for HIT antibodies if the platelet count falls by > 50%, and/or a thrombotic event occurs, between postoperative days 5 and 14 (inclusive; day of cardiac surgery day 0) [Grade 1C]. 2.0 Treatment of HIT 2.1 Nonheparin Anticoagulants for Treating HIT (With or Without Thrombosis) For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], bivalirudin [Grade 2C]) over the further use of UFH or LMWH therapy or initiation/continuation of a VKA (Grade 1B) For patients receiving lepirudin, the initial lepirudin infusion rate should be no higher than 0.10 mg/kg/h (patients with creatinine < 90 mol/l), with lower infusion rates for patients with higher serum creatinine levels (creatinine, 90 to 140 mol/l: starting infusion rate, 0.05 mg/kg/h; creatinine, 140 to 400 mol/l: starting infusion rate, 0.01 mg/kg/h; creatinine > 400 mol/l: starting infusion rate, mg/kg/h) [Grade 1C]. Furthermore, we recommend that the initial IV bolus either be omitted or, in case of perceived life- or limbthreatening thrombosis, be given at a reduced dose (0.2 mg/kg) [Grade 1C]. Further, we recommend that APTT monitoring be performed at 4-h intervals until it is apparent that steady state within the therapeutic range (1.5- to 2.0- times patient baseline [or mean laboratory] APTT) is achieved (Grade 1C) When argatroban is used to treat patients who have heart failure, multiple organ system failure, or severe anasarca or who are postcardiac surgery, we suggest beginning the initial infusion at a rate between 0.5 and 1.2 g/kg/ min, with subsequent adjustments using the APTT, over the usual recommended starting dose of 2.0 g/kg/min (Grade 2C) When danaparoid is used to treat patients with strongly suspected (or confirmed) HIT, we recommend a therapeutic-dose regimen (see text) administered (at least initially) by the IV route over prophylactic-dose regimens or initial SC administration (Grade 1B) For patients with strongly suspected or confirmed HIT, whether or not there is clinical evidence of lower-limb DVT, we recommend routine ultrasonography of the lower-limb veins for investigation of DVT over not performing routine ultrasonography (Grade 1C). 2.2 VKAs Management of Direct Thrombin Inhibitor VKA Overlap For patients with strongly suspected or confirmed HIT, we recommend against the use of VKA (coumarin) therapy until after the platelet count has substantially recovered (ie, usually to at least /L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low, maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) rather than with higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the INR has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin 342S

4 anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B) Reversal of VKA Anticoagulation For patients receiving a VKA at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C]. 2.3 LMWH for HIT For patients with strongly suspected HIT, whether or not complicated by thrombosis, we recommend against use of LMWH (Grade 1B). 2.4 Prophylactic Platelet Transfusions for HIT For patients with strongly suspected or confirmed HIT who do not have active bleeding, we suggest that prophylactic platelet transfusions should not be given (Grade 2C). 3.0 Special Patient Populations 3.1 Patients With Previous HIT Undergoing Cardiac or Vascular Surgery For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, we recommend the use of UFH over a nonheparin anticoagulant (Grade 1B) For patients with a history of HIT who are antibody positive by platelet factor 4 (PF4)-dependent enzyme immunoassay (EIA) but antibody negative by washed platelet activation assay, we recommend the use of UFH over a nonheparin anticoagulant (Grade 2C). Remark: Preoperative and postoperative anticoagulation, if indicated, should be given with a nonheparin anticoagulant. 3.2 Patients With Acute or Subacute HIT Undergoing Cardiac Surgery For patients with acute HIT (thrombocytopenic, HIT antibody positive) who require cardiac surgery, we recommend one of the following alternative anticoagulant approaches (in descending order of preference): delaying surgery (if possible) until HIT has resolved and antibodies are negative (then see Recommendation ) or weakly positive (then see Recommendation ) [Grade 1B]; using bivalirudin for intraoperative anticoagulation during cardiopulmonary bypass (if techniques of cardiac surgery and anesthesiology have been adapted to the unique features of bivalirudin pharmacology) [Grade 1B] or during off-pump cardiac surgery (Grade 1B); using lepirudin for intraoperative anticoagulation (if ECT is available and patient has normal renal function and is judged to be at low risk for postcardiac surgery renal dysfunction) [Grade 2C]; using UFH plus the antiplatelet agent epoprostenol (if ECT monitoring is not available or renal insufficiency precludes lepirudin use) [Grade 2C]; using UFH plus the antiplatelet agent, tirofiban (Grade 2C); or using danaparoid for intraoperative anticoagulation for off-pump coronary artery bypass surgery (Grade 2C) over performing the surgery with UFH when platelet-activating anti-pf4/heparin antibodies are known to be present in a patient with acute or recent HIT For patients with subacute HIT (platelet count recovery, but continuing HIT antibody positive), we recommend delaying surgery (if possible) until HIT antibodies (washed platelet activation assay) are negative, then using heparin (see Recommendation ) over using a nonheparin anticoagulant (Grade 1C). If surgery cannot be delayed, we suggest the use of a nonheparin anticoagulant (see Recommendation ) over the use of UFH (Grade 2C). 3.3 Percutaneous Coronary Interventions For patients with strongly suspected (or confirmed) acute HIT who require cardiac catheterization or percutaneous coronary intervention (PCI), we recommend a nonheparin anticoagulant (bivalirudin [Grade 1B], argatroban [Grade 1C], lepirudin [Grade 1C], or danaparoid [Grade 1C]) over UFH or LMWH (Grade 1B) For patients with previous HIT (who are antibody negative) who require cardiac catheterization or PCI, we suggest use of a nonheparin anticoagulant (see Recommendation ) over UFH or LMWH (Grade 2C). Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse effect of heparin that is important because of its strong association with venous and arterial thrombosis. 1 4 Patients treated with heparin in whom HIT develops constitute a cohort with substantially increased thrombotic risk, both in relative (odds ratio [OR] for thrombosis, 20 to ) and absolute (thrombosis risk, 30 to 75% 1 10 ) terms, depending on the patient population affected. CHEST / 133 / 6/ JUNE, 2008 SUPPLEMENT 343S

5 Because the diagnosis is based on both clinical and serologic grounds, clinicians should consider HIT a clinicopathologic syndrome Thus, neither thrombocytopenia or thrombosis without the presence of heparin-dependent antibodies, nor the isolated presence of antibodies without thrombocytopenia, thrombosis, or other clinical sequelae, meet the criteria for HIT. Rather, clinicians make a diagnosis of HIT when any of the following events occurs in association with the presence of HIT antibodies detected by in vitro assays: (1) an otherwise unexplained platelet count fall (defined by various investigators as a minimum platelet count fall of 30%, 15,16 40%, 17 or 50% 2 even if the platelet count nadir remains /L (note: the baseline platelet count is not necessarily the preheparin platelet count, but rather the highest platelet count during the 2-week period that follows initiation of heparin therapy and that immediately precedes the platelet count decline indicating HIT); (2) venous or arterial thrombosis (most often, deep venous thrombosis [DVT], pulmonary embolism [PE], limb artery thrombosis, thrombotic stroke, myocardial infarction, adrenal hemorrhagic necrosis [indicating adrenal vein thrombosis]); (3) skin lesions at heparin injection sites 18 ; or (4) acute systemic (anaphylactoid) reactions (eg, fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest) that occur after IV heparin bolus administration. 7 Diagnostic specificity can be further increased by use of a sensitive washed platelet activation assay; a positive platelet activation assay is much more specific for clinical HIT than a positive platelet factor 4 (PF4)-dependent immunoassay With such a clinicopathologic viewpoint, clinicians can diagnose clinical HIT even when the patient s platelet count does not fall by as much as 30% (eg, a patient with heparin-induced necrotizing skin lesions and adrenal necrosis associated with formation of plateletactivating anti-pf4/heparin antibodies 18 ). 21,24 Indeed, in about 25% of HIT patients, a thrombotic event during heparin treatment precedes the subsequent HIT-associated platelet count fall. 1,16 The neoepitopes recognized by HIT antibodies are located on PF4, and are formed when PF4 binds to heparin HIT antibodies activate platelets intravascularly, causing release of platelet microparticles and increased thrombin generation. However, only a subset of anti-pf4/heparin antibodies activate platelets, 19,20,28 which explains the greater diagnostic specificity of certain platelet activation assays (eg, platelet serotonin release assay [SRA], heparininduced platelet activation (HIPA) assay] for HIT compared with the PF4-dependent EIA. 19,20,23,29 There is a correlation between the degree of reactivity in the EIA, expressed in optical density (OD) units, and the presence of platelet-activating anti- PF4/heparin antibodies. Thus, the greater the magnitude of a positive EIA test result, the greater the likelihood that the patient has HIT, given a certain pretest probability. However, a very strong EIA test result does not necessarily mean that plateletactivating IgG antibodies are present; conversely, only about 5 to 10% of sera showing reactivity 0.4 to 1.0 OD U in an EIA nonetheless contain strong platelet-activating antibodies. 29 This chapter is organized into sections on the recognition, treatment, and prevention of HIT. The scope of our recommendations include platelet count monitoring for HIT as well as management of HIT, both in patients detected by thrombocytopenia alone ( isolated HIT ) and in patients who present with HIT-associated thrombosis. The interrelatedness of platelet count monitoring and treatment recommendations is clear when one considers that isolated HIT (a patient population with substantial risk of thrombosis) by definition can be detected only by platelet count monitoring. Furthermore, even in patients with thrombosis complicating HIT, the availability of serial platelet counts often provides the key information to prompt consideration of the diagnosis of HIT. Table 1 lists the inclusion and exclusion criteria for the studies used to formulate our recommendations. 1.0 Recognition of HIT 1.1 Platelet Count Monitoring for HIT HIT occurs most commonly in certain patient populations, such as postoperative patients who receive standard, unfractionated heparin (UFH) for 1 week (for review, see Lee and Warkentin 6 ). One definition classifies an adverse reaction as common if its incidence is 1%. 30 In other clinical settings, the estimated risk of HIT can be described as uncommon (0.1 to 1%) or rare ( 0.1%). 30 As described later, there is evidence that initial isolated HIT has a substantial risk of evolving to symptomatic and fatal thrombosis. Further, prospective cohort studies (with historical controls) suggest that antithrombotic therapy reduces the risk of thrombosis in patients with isolated HIT. In addition, HIT can lead to life- and limb-threatening complications, a risk that could increase with delay in diagnosis or increase in heparin dose (to treat unrecognized HIT-associated thrombosis), or through use of warfarin. These considerations suggest that routine platelet count monitoring for HIT is appropriate in at least some clinical situations, and that the greater the risk of HIT, the stronger the rationale for regular monitoring. Another consideration that supports a role for platelet count monitoring is that HIT antibody seroconversion and resulting typical-onset HIT usually 344S

6 Section Table 1 Question Definition and Study Eligibility Criteria (Section: Introduction) Inclusion Criteria Population Intervention(s) or Exposure Outcome Methodology Exclusion Criteria 1.1 Hospitalized medical, surgical, or obstetric patients 1.2 Cardiac surgery patients undergoing on-pump and off-pump surgery 2.1 HIT patients (with or without thrombosis) 2.2 HIT patients (with or without thrombosis) 2.3 HIT patients (with or without thrombosis) 2.4 HIT patients (with or without thrombosis) 3.1 Patients with previous HIT undergoing cardiac surgery 3.2 Patients with acute or subacute HIT undergoing cardiac surgery 3.3 Patients with previous or acute HIT undergoing PCI 3.4 Patients with acute HIT undergoing hemodialysis 4.1 Hospitalized medical, surgical, or obstetric patients; cardiac surgery patients UFH or LMWH for 5 20 d vs no anticoagulation No anticoagulation vs anticoagulation (UFH, LMWH, fondaparinux) after surgery Non-heparin anticoagulation (lepirudin, argatroban, bivalirudin, danaparoid, or fondaparinux) VKAs (coumarins) LMWH Platelet transfusions vs no platelet transfusions Repeat heparin exposure Anticoagulant approaches during cardiac surgery: lepirudin, argatroban, danaparoid, bivalirudin, UFH plus epoprostenol, UFH plus tirofiban Non-heparin anticoagulation Non-heparin anticoagulation Comparison of UFH and LMWH/fondaparinux HIT (platelet count decrease 30%) and/or new thrombosis/skin lesions (secondary to plateletactivating anti-pf4/heparin antibodies); anti-pf4/heparin antibody formation (platelet activation assays and/or PF4/polyanion EIA) HIT; HIT-associated VTE; HIT antibody formation New thrombosis; mortality; limb amputation; composite of above; drug anaphylaxis VKA therapy-associated thrombosis, including venous limb gangrene, skin necrosis Thrombosis; platelet count recovery New thrombosis Recurrence of HIT; repeat formation of HIT antibodies Procedural success (as defined by study authors) Procedural success (as defined by study authors) Procedural success (as defined by study authors) Frequency of HIT (using explicit criteria); frequency of HIT antibody formation Metaanalyses, RCTs, cohort studies Metaanalyses; RCTs; cohort studies RCTs; cohort studies Cohort studies Cohort studies Cohort studies and case series Prospective cohort studies; retrospective cohort studies Prospective cohort studies; retrospective cohort studies Prospective cohort studies; retrospective cohort studies Retrospective cohort studies Metaanalyses; RCTs; nonrandomized controlled studies; retrospective cohort studies 25 patients 50 patients 25 patients (no exclusions for reports on drug-associated anaphylaxis) Patients without HIT antibodies 25 patients 5 patients 5 patients 5 patients 5 patients 5 patients 100 patients occur during specific time periods following initiation of heparin, namely days 5 to 10 (seroconversion and initial platelet count fall) and days 7 to 14 (reaching a threshold defining thrombocytopenia), when the first day of the immunizing heparin exposure is considered to be day 0. 1,2,6,7,31,32 (Day 4 can be included within the period of platelet count monitoring for HIT because it can provide a com- CHEST / 133 / 6/ JUNE, 2008 SUPPLEMENT 345S

7 parative preimmunization reference point.) Further, rapid-onset HIT (in which the platelet count fall begins within 24 h of starting heparin) is strongly associated with recent heparin exposure (within the past 100 days, and especially the last 30 days). 31,32 The frequency of HIT among patients exposed to heparin is highly variable, and is influenced by the heparin preparation (bovine UFH porcine UFH low-molecular-weight heparin [LMWH]), 19,20,33 41 the type of heparin-exposed patient population (postsurgery medical pregnancy), 19,20,41 46 duration of heparin exposure, 7 and patient sex (female male). 41 Thus, whether to perform platelet count monitoring, and the intensity of such monitoring, depends on these considerations, particularly heparin and patient type and the duration of heparin use. Therefore, it is appropriate to perform platelet count monitoring in certain clinical situations, and to focus platelet count monitoring during those times when HIT usually occurs. Furthermore, the rationale for platelet count monitoring is stronger when monitoring is relatively easy (ie, in a hospital inpatient), and weaker when monitoring is more difficult (ie, out-patient settings. Table 2 summarizes the various risk factors for HIT, and classifies risk into three different groups: high ( 1.0%), intermediate (0.1 to 1.0%), and low ( 0.1%). 1,2,4,6,15,17,19,20,34 71 A potential downside of platelet count monitoring is that patients with a decrease in platelet counts for reasons other than HIT may be wrongly suspected of having this diagnosis. As the alternative nonheparin anticoagulants have a relatively high risk of bleeding, there is the potential for treatment-related adverse events as a consequence of platelet count monitoring. Underlying Values and Preferences: The following recommendations regarding monitoring of platelet count share the same underlying values and preferences, as follows. The recommendations place a high value on the possible benefits of early diagnosis and consequent early treatment of HIT to prevent sequelae and a lower value on the burden and cost of monitoring platelet counts, including the consequences of further investigation and management of the high proportion of patients with a significant fall in platelet count who do not have HIT and the risks associated with unnecessary withdrawal of heparin and unnecessary use of alternative agents with a higher bleeding risk. Recommendation 1.1. For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients receiving heparin who have an estimated risk of HIT of 0.1 to 1.0%, we suggest platelet count monitoring over no platelet count monitoring (Grade 2C) Platelet Count Monitoring of Patients Recently Treated With Heparin Rapid-onset HIT refers to patients who have a large platelet count fall attributable to HIT antibodies within 24 h of starting heparin. 31,32 Contrary to popular assumption, this phenomenon is not caused by an anamnestic immune response, but rather results from the administration of heparin to a patient who has already-circulating HIT antibodies that resulted from a recent heparin exposure. 31,32 As a general rule, exposure within the past 100 days (and especially within the last month) is associated with the phenomenon of rapid-onset HIT. Recommendation For patients who are starting UFH or LMWH treatment and who have received UFH within the past 100 days, or those patients in whom exposure history is uncertain, we recommend obtaining a baseline platelet count and then a repeat platelet count within 24 h of starting heparin over not obtaining a repeat platelet count (Grade 1C) Anaphylactoid Reactions After IV UFH Bolus Rarely, patients develop acute inflammatory (eg, fever, chills) or cardiorespiratory (eg, hypertension, tachycardia, dyspnea, chest pain, cardiorespiratory arrest) symptoms and signs within 30 min following an IV heparin bolus. 7,47 Also termed acute systemic reactions, these can also mimic acute PE (pseudopulmonary embolism 48 ) and strongly suggest acute in vivo platelet activation secondary to HIT. This presentation mandates a prompt platelet count measurement, as an abrupt platelet count fall in this clinical context supports the diagnosis of HIT. The platelet count drop is frequently transient, 2 and thus a delay in determining the platelet count, especially if heparin is stopped, may result in a missed diagnosis. Recommendation For patients in whom acute inflammatory, cardiorespiratory, neurologic, or other unusual symptoms and signs develop within 30 min following an IV UFH bolus, we recommend 346S

8 Table 2 Risk Factors for HIT: Implications for Platelet Count Monitoring (Section: 1.1)* Relative Importance of Risk Factor Risk Factors Major (OR 5) Moderate (OR 3 5) Minor (OR 1 3) Heparin duration 4 d Yes Recent heparin (past 100 d) Yes UFH LMWH Yes Postsurgery medical obstetric Dose of heparin Immunizing: prophylaxis therapeutic Manifesting: therapeutic prophylaxis flushes Gender: female male Examples of patient groups with risk estimated to be 1% Postoperative patients receiving prophylactic-dose UFH 4d Postoperative patients receiving therapeutic-dose UFH 4d# Examples of patient groups with risk estimated to be 0.1 1% Medical/obstetric patients receiving prophylactic or therapeutic-dose UFH 4d Postsurgery patients receiving LMWH 4d Postsurgery patients receiving UFH flushes 4d Medical/obstetric patients receiving LMWH after first receiving UFH Examples of patients groups with risk estimated to be 0.1% Medical/obstetric patients receiving LMWH 4d** Medical/obstetric patients receiving only heparin flushes Any patient receiving UFH or LMWH 4d *Based upon assessment of the published literature. 1,2,4,6,15,17,19,20,34 71 Risk declines after 14 days (in the absence of intervening surgery). Risk of rapid-onset HIT if heparin is restarted in a patient exposed within the past 100 days (and especially the last 30 days). Difference in risk between UFH and LMWH best established in postsurgery patients and in females. Theoretically, stoichiometric concentrations of PF4/UFH and PF4/LMWH are most likely to be achieved at prophylactic doses. Among patients who have HIT antibodies, higher doses of heparin usually result in greater platelet count falls. #Best established in post-cardiac surgery patients. **One study 38 suggested that the frequency of HIT in medical patients receiving LMWH could be between 0.1 1%, but this study is a statistical outlier and its conclusions remain to be confirmed. 39,41 Yes Yes Yes Yes performing an immediate platelet count measurement, and comparing this value to recent prior platelet counts, over not performing a platelet count (Grade 1C) Platelet Count Monitoring in Patients Receiving Therapeutic-Dose UFH For patients receiving porcine UFH in therapeutic doses, by either the IV or subcutaneous (SC) route, for the treatment of venous or arterial thrombosis, the risk of HIT has been estimated to be at most about 1%, 6 based on a review of studies of the frequency of HIT in patients receiving porcine UFH for venous thromboembolism. 4,36,49 62 However, the two most recent studies 4,36 identified only 1 patient with HIT among 594 treated with therapeutic-dose UFH, suggesting that the frequency among this patient population is likely 1%. Recommendation For patients who are receiving therapeutic-dose UFH, we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C) Platelet Count Monitoring in Postoperative Patients Receiving UFH Antithrombotic Prophylaxis (Highest Risk Group for HIT) Patient groups at the highest risk of HIT (1 to 5%) include postoperative orthopedic, cardiac, and vascular surgery patients who are receiving UFH for 1 to 2 weeks, 15,17,19,20,33,63 67 and, likely, other postsurgery patient populations. Recommendation For patients who are receiving postoperative antithrombotic prophylaxis with UFH, ie, the patient population at highest risk for HIT (HIT risk > 1%), we suggest at least everyother-day platelet count monitoring between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C). CHEST / 133 / 6/ JUNE, 2008 SUPPLEMENT 347S

9 While we gave a strong recommendation overall in favor of performing platelet count monitoring when the risk of HIT was judged to be > 1% (see Recommendation 1.1), our recommendation for the specific intensity of platelet count monitoring in this and other patient populations (see also Recommendations and 1.1.5) have been given a weak (Grade 2) recommendation because no study exists comparing outcomes using any particular platelet count monitoring strategy. Our suggestion to perform every-other-day monitoring takes into account the observation that platelet count declines in HIT, when they occur, are relatively rapid (median of 2 to 3 days from the postoperative peak to a > 50% platelet count decline). 1,2, Platelet Count Monitoring in Patients in Whom HIT is Infrequent (0.1 to 1%) There are several patient groups in which the risk of HIT can be classified as uncommon (ie, 0.1 to 1%). These include medical (including patients with acute coronary syndrome) or obstetrical patients receiving prophylactic-dose UFH 4,6,46,60 62,68 70 ; postoperative patients receiving LMWH 1,2,6,17,19,20,63,66 ; postoperative/critical care patients receiving UFH flushes 6,71 ; and, theoretically, medical patients receiving LMWH after having received one or more preceding doses of UFH. In some settings (eg, patients receiving outpatient LMWH), it may be impractical to obtain platelet counts. Thus, less frequent (or no) platelet count monitoring may be appropriate in these patients, especially if the risk is thought to be closer to 0.1% than 1% (eg, postoperative patients receiving LMWH) and if the patient is instructed to contact the physician promptly if signs or symptoms of venous thromboembolism (the most common complication of HIT) occur or painful skin lesions develop at the heparin injection sites (see also Recommendation 1.1.8). Recommendation For medical/obstetrical patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH flushes, or medical/ obstetrical patients receiving LMWH after first receiving UFH (estimated HIT risk, 0.1 to 1%), we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first), when practical, over less frequent platelet count monitoring (Grade 2C) Platelet Count Monitoring When HIT is Rare ( 0.1%): UFH and LMWH In medical and obstetrical patients receiving LMWH, the risk of HIT appears to be rare ( 0.1%). 36,37,39,42 45 For example, only one possible case 43 of HIT was observed among 1,167 pregnancies treated with LMWH in three studies ; a more recent review 45 of LMWH use during 2,777 pregnancies identified no cases of HIT. Although fewer data exist with respect to medical patients receiving LMWH or UFH as flushes (eg, oncology patients with indwelling catheters), 72,73 the experience of the authors is that HIT is rare in this setting. However, one prospective, multicenter study 38 of LMWH administered to medical patients reported the frequency of HIT to be 0.8%. Limitations of this study suggest, however, that it provides an overestimate of HIT incidence: (1) not all patients underwent testing with the more specific platelet activation assays, and (2) some of the clinical features (eg, early onset of thrombocytopenia) were not characteristic of this adverse drug reaction. Furthermore, the data represent a statistical outlier compared with other studies, 39,41 and in our view further studies are required before recommending that platelet count monitoring be performed routinely in medical patients receiving LMWH. Recommendation For medical/obstetrical patients who are receiving only LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C). Underlying Values and Preferences: This recommendation places a lower value on the rare diagnosis and early treatment of HIT to prevent sequelae and a higher value on the burden and cost of monitoring platelet counts Platelet Count Monitoring When HIT is Rare ( 0.1%): Fondaparinux Fondaparinux is an indirect (antithrombinmediated) inhibitor of factor Xa modeled after the pentasaccharide region of heparin. A syndrome resembling immune HIT was not reported in any of the regulatory trials for this anticoagulant in various clinical settings (eg, orthopedic surgery, 74 treatment of venous thromboembolism 75,76 ). However, anti-pf4/heparin antibodies some with platelet-activating properties have been observed to occur in association with fondaparinux thromboprophylaxis in a frequency similar to that seen with the LMWH enoxaparin. 77,78 348S

10 Unlike the situation with UFH or enoxaparin, these antibodies as well as antibodies obtained from patients with typical HIT do not bind well to PF4 in vitro in the presence of fondaparinux, even though they recognize well the epitopes on PF4 in the presence of UFH or LMWH Further, several dozen patients with putative HIT have been reported to have shown platelet count recovery during administration of fondaparinux It therefore seems that the risk of inducing a syndrome resembling immune HIT is negligible. To our knowledge, only one possible case of HIT that occurred in association with postoperative fondaparinux thromboprophylaxis has been reported after 4 years in the marketplace. 85 In our view, this negligible frequency of immune thrombocytopenia indicates that routine platelet count monitoring for HIT should not be performed. Recommendation For patients who are receiving fondaparinux thromboprophylaxis or treatment, we recommend that clinicians do not use routine platelet count monitoring (Grade 1C) Management of Patients in Whom Platelet Counts Are Not Monitored Clinicians should consider informing patients receiving UFH or LMWH about the potential for the adverse effect of HIT. For patients not under close platelet count monitoring, clinicians should describe the most common resulting signs and symptoms, ie, new thrombosis and painful skin lesions at the heparin injection sites. Outpatients should be advised to seek medical advice immediately if these events occur. This will increase awareness of HIT in both the patient and the treating physician. Recommendation In outpatients who will receive heparin prophylaxis or treatment, informed consent should include HIT and its typical sequelae (new thrombosis, skin lesions) and the patient should be advised to seek medical advice if these events occur (Grade 2C) Screening for Subclinical HIT Antibody Seroconversion Prospective studies of HIT and HIT antibody formation 1,2,6,19,20,34 36,67,86 indicate that HIT occurs in a minority of patients who form anti-pf4/heparin antibodies. The serologic profile in about 99% of patients with clinical HIT is positive testing in both of two sensitive and complementary assays: (1) platelet activation (or functional ) assay using washed platelets (eg, 14 C-SRA, HIPA test), or (2) PF4- dependent EIA. 19,20,87 However, even though both assays are sensitive in detecting HIT antibodies, neither is completely specific for the HIT syndrome (although the functional assays are far more specific than the EIA). 13 Consequently, serology is more effective in ruling out a possible diagnosis of HIT than in confirming the diagnosis, ie, the negative tests have a very low likelihood ratio, but positive tests only a moderately high likelihood ratio. However, the strength of a positive test result provides useful diagnostic information regarding the likelihood of HIT. For example, a strong positive test result (eg, 90% serotonin release or 2.0 absorbance units) was associated with a high likelihood ratio for HIT in patients after orthopedic surgery (approximately 100), whereas a weak positive test result (eg, absorbance units in one study using an in-house PF4-dependent EIA that detected IgG class antibodies) was associated with a relatively low risk for HIT. 19,21,29 For patients after cardiac surgery, the corresponding risks for HIT for strong and weak serologic results are likely to be lower. 21,29 The risk of HIT is even lower when using commercial EIAs that detect antibodies of all three Ig classes. The diagnostic interpretation of these laboratory tests must be made in the context of the clinical estimation of the pretest probability of HIT. 13,21,88 Further, prospective data indicate that an increased risk of thrombosis occurs in the group of patients whose platelet count has fallen in relation to HIT antibody formation (ie, those with clinical HIT) rather than in patients who develop antibodies without a significant platelet count decline. 1,2 In our view, it is not useful to perform anti-pf4/heparin antibody testing in the absence of clinical indication of HIT, by either an unexpected fall in the platelet count or an unexpected clinical event. Thus, routine platelet count monitoring, rather than routine anti- PF4/heparin antibody studies, is most useful (and most practical) to identify patients who are at risk for developing thrombosis because of immunization triggered by heparin therapy. In addition, there is no evidence that routine testing for anti-pf4/heparin antibodies prior to cardiac or vascular surgery in the absence of thrombocytopenia or thrombosis or other clinical evidence of HIT leads to identification of clinically significant antibodies or improves patient outcomes. In our view, such routine testing is much more likely to identify subclinical antibodies that do not pose inwww.chestjournal.org CHEST / 133 / 6/ JUNE, 2008 SUPPLEMENT 349S

11 creased risk for perioperative complications attributable to the intraoperative or postoperative use of heparin. Recommendation In patients who receive heparin, or in whom heparin treatment is planned (eg, for cardiac or vascular surgery), we recommend against routine HIT antibody testing in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to a potential diagnosis of HIT (Grade 1C) When Should HIT Be Suspected? Retrospective and prospective studies suggest that 90% of patients with clinical HIT have a platelet count fall that is 50% during their heparin treatment. 2,12 In patients with HIT who have lesser degrees of platelet count decline, almost all are identified because of thrombotic complications or other sequelae, such as heparin-induced skin lesions or anaphylactoid reactions following IV bolus UFH. 21 The pretest probability of HIT should also be influenced by the temporal features of the platelet count fall and by the likelihood of other possible alternative diagnoses to explain the thrombocytopenia (eg, perioperative hemodilution, sepsis/ multiorgan system dysfunction, cancer-associated coagulopathy, glycoprotein IIb/IIIa antagonist administration, clearance of previously transfused platelets). 21,89 PE poses a special problem: Whereas HIT is strongly associated with PE (OR, 40), 7 PE itself can be associated with prominent thrombocytopenia (with associated consumptive coagulopathy) even in the absence of HIT antibodies, 89,90 thus emphasizing the important diagnostic role of laboratory testing for HIT antibodies. Clinicians should consider a diagnosis of HIT when thrombocytopenia (defined subsequently) occurs with a temporal pattern consistent with heparininduced immunization, ie, platelet count fall that begins 5 to 10 days (or thrombocytopenia that occurs 7 to 14 days) after starting a course of heparin therapy (first day of heparin day 0), or when thrombosis or other sequelae of HIT occur in patients treated (or recently treated) with heparin. 21 The pretest estimation of the probability of HIT is also influenced by the pattern of the platelet count fall and by the likelihood of other possible alternative diagnoses to explain the thrombocytopenia. 21 The strong association between HIT and thrombosis indicates that clinicians should suspect HIT and draw a platelet count (and compare the result with previous values) in a patient who develops symptomatic venous or arterial thrombosis while receiving heparin prophylaxis or treatment, or within several days after heparin prophylaxis or treatment. A recent study 16 found that in approximately one quarter of patients recognized with HIT, HIT-associated thrombosis preceded the development of thrombocytopenia by 1 day or a few days. In such cases, administration of higher doses of heparin to treat the thrombosis can unmask HIT. 91 About two thirds of HIT patients evince typicalonset HIT, ie, the platelet count begins to fall 5 to 10 days after starting heparin, 31,32 although thrombocytopenic levels (eg, 50% fall or to /L) are usually not reached until a few days later (about 7 to 14 days after beginning heparin). In about 25 to 30% of patients, the platelet count falls abruptly on beginning a course of heparin. 31 Such rapid-onset HIT occurs in patients who recently (within the previous 100 days) have been exposed to heparin, 31,32 and represents abrupt onset of platelet activation in a patient who has residual circulating HIT antibodies related to the recent prior heparin exposure. In about 3 to 5% of patients with HIT, the onset of thrombocytopenia begins several days after heparin has been stopped (delayed-onset HIT) This last syndrome is consistent with a transient autoimmune nature of HIT, as these patients have PF4/heparinreactive antibodies that can activate platelets even in the absence of heparin. 92,99 Sometimes even relatively minor exposures to heparin ( 5,000 U), particularly when given in a perioperative or inflammatory setting, have resulted in this syndrome. In December 2006, the US Food and Drug Administration (FDA) notified health-care professionals of revisions to the WARNINGS section of the prescribing information for heparin to inform clinicians of the possibility of delayed onset of HIT. Definition of Thrombocytopenia in HIT: The majority of postoperative patients who acquire HIT sustain an otherwise unexplained 50% fall in the platelet count from the postoperative peak during the second week following surgery. 2 This reduction occurs on a background of the normal pattern of a rising platelet count expected between postoperative days 4 to 14 (transient postoperative thrombocytosis). 1,2 Thus, in postoperative HIT, the serial platelet counts form an inverted V as the initial platelet count recovery that begins about 2 to 3 days following surgery transforms unexpectedly to a falling platelet count a few days later. 1,2,7 In contrast, in medical patients, the platelet count fall begins or accelerates from day 5 onwards, usually without a preceding profile of a rising platelet count. 4 On occasion, the platelet count declines by 50% even though the clinical and serologic findings otherwise strongly suggest HIT-associated thrombosis. 12,18 350S

12 Although there are fewer data on an appropriate definition of HIT applicable to medical patients, 4 it appears that a proportional ( 50%) fall in platelet count beginning between days 5 and 14 of heparin therapy is appropriate. In our opinion, such a threshold avoids trivial platelet count declines that might be detected if an absolute threshold, such as /L, is used to define thrombocytopenia, especially as transient thrombocytosis does not often occur in medical patients. We are making a strong recommendation regarding the approach to defining thrombocytopenia in HIT because there is good evidence that a proportional fall in platelet count of 50% is superior to an absolute threshold of /L for the detection of HIT, at least in postoperative patients (improved sensitivity for HIT without loss of diagnostic specificity). 2,7 However, no single definition of thrombocytopenia is appropriate in all clinical situations. Recommendation For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by > 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). 1.2 Special Situation: Anticoagulant Prophylaxis and Platelet Count Monitoring After Cardiac Surgery The risk of symptomatic venous thrombosis is relatively low in postcardiac surgery patients, even when no antithrombotic prophylaxis is given (although subclinical DVT can be detected in 20% of patients). 100 Many cardiac surgery centers give antithrombotic prophylaxis with UFH (in North America more than in Europe) or LMWH (Europe more than North America). Even if anticoagulant prophylaxis is not routinely given, individual patients who have undergone cardiac surgery may receive anticoagulants because of a prosthetic mechanical valve or unexpected complications such as prolonged postoperative atrial fibrillation, thrombotic stroke, or prolonged immobilization. The risk of anti-pf4/heparin antibody formation is especially high in this population of cardiac surgery patients, ranging from 35 to 65% by days 7 to 10, even when postoperative anticoagulant prophylaxis with heparin is not given 17,19,65 67,101 or if off-pump surgery is performed. 35 More importantly, the absolute risk of clinical HIT in such patients who receive UFH following surgery ranges from 1 to 3%. 6,17,65 67,102,103 Finally, this patient population has a relatively high burden of atherosclerosis, and appears to be at a disproportionately higher risk for life- and limb-threatening arterial complications compared with other patient populations. 7,16 An ongoing nonrandomized comparison 17,66 between UFH and LMWH antithrombotic prophylaxis after cardiac surgery found a substantially lower frequency of HIT with LMWH use than with UFH use (11/437, or 2.5%, vs 8/1,874, or 0.4%; p ). However, there were differences in the patient populations that led to one or the other drug being selected for use. Thus, whether LMWH reduces the risk of HIT in this patient population though likely remains unproven. Further, HIT antibodies resulting from UFH therapy frequently cross-react with LMWH, and because patients receiving LMWH after cardiac surgery invariably received UFH during cardiac surgery, there is the potential for HIT to occur more frequently with LMWH in this patient population than in other clinical settings. However, because (to our knowledge) there are no formal studies proving that routine anticoagulant prophylaxis, either with UFH or LMWH, is safe and effective following cardiac surgery, it is difficult to provide any firm recommendations. Given the known high risk of HIT in this patient population, we believe that monitoring for HIT is especially important if surgeons prescribe postoperative UFH or LMWH. 102 A practical problem in monitoring for HIT after cardiac surgery is that major hemodilution occurs both during and in the first several days following cardiac surgery. This perioperative platelet count decrease typically attains its nadir 2 days after surgery. However, HIT is rare in the first 4 days after cardiac surgery, even in patients who have received heparin during the preoperative period. This is because HIT resulting from heparin exposure during angiography or for treatment of acute coronary syndrome is infrequent ( 1%), whereas postoperative dilutional thrombocytopenia occurs universally. Thus, it is difficult on clinical grounds to identify the occasional case of HIT beginning soon after cardiac surgery (in which immunization resulted from preoperative heparin exposure). In contrast, HIT is a relatively likely explanation for a platelet count fall 50% that begins from postoperative day 5 onwards. This is because the circumstances of cardiac surgery are a frequent stimulus for HIT antibody generation, and because the typical onset of HIT (beginning 5 to 10 days after cardiac surgery) coincides with the time period in which the platelet count typically is rising CHEST / 133 / 6/ JUNE, 2008 SUPPLEMENT 351S